We further examined our hypothesis that the
We further examined our hypothesis that the activation of CRF and CCK systems is responsible for the enhanced anxiety-like behavior induced by immobilization stress using two antagonists to block the expression of CRF1 and CCK2 receptors. It was found that CCK2 receptor antagonist CR2945 or CRF1 antagonist antalarmin partially reversed the enhanced anxiety-like behavior induced by 30-min immobilization, which is in agreement with a study from Henry et al. (2006), who demonstrated that the administration of the CRF1 antagonist antalarmin into the central amygdala reduced the anxiogenic effect of the 30-min immobilization stress. Although the blockade of CRF1 or CCK2 receptor alone only partially reversed the enhancement of anxiety-like behavior induced by immobilization stress, the combined treatment of CR2945 and antalarmin could fully block this enhancement, suggesting the synergetic effects of CRF and CCK systems in the immobilization-induced anxiety in mice.
Introduction Cardiovascular response to acute and chronic stimulus is mediated by central regulatory mechanisms that control the sympathetic outflow to the cardiovascular system in the short and long term (Dampney et al., 2002) and mainly involves feedback regulation and homeostatic neural mechanisms. The central mechanisms controlling the sympathetic tone consist in a complex response to an adaptive behavior, such as those involved in response to stress (Peliki et al., 2014). The paraventricular nucleus (PVN) is the main hypothalamic nucleus regulating the activation of the hypothalamic–pituitary–adrenal (HPA) axis and the neuroendocrine control of visceral autonomic functions. PVN neurons project to the intermediolateral cell column of the thoraco-lumbar spinal cord and to supraspinal regions, such as the ventrolateral medulla (VLM). This brainstem region contains sympathetic pre-motor neurons involved in the regulation of the cardiovascular activity (Ally, 1998, Dampney et al., 2000). The development of opioid addiction involves complex adaptive changes in the opioid receptors and associated signaling systems leading to neuronal plasticity in specific o-Phenanthroline regions involved in the regulation of the cardiac activity, such as PVN and VLM (Dampney et al., 2000, Kc and Dick, 2010). In addition, to the neurobehavioral consequences of addiction, there is a strong association between addiction and severe medical disorders including cardiovascular disease (Frishman et al., 2003, Nerantzis et al., 2011). Despite the clinical relevance of this association little is known about the pathophysiology or mediators underlying this comorbidity. Stress is a common risk factor for both addiction and cardiovascular disease, like stress, morphine withdrawal leads to the activation of two systems: the catecholaminergic system and the HPA axis. Activation of the former results in enhanced circulating catecholamine levels that can damage the heart (Kasch, 1987). The extrahypothalamic stress system, more specifically, the extended amygdala, which consists of several basal forebrain structures, including the bed nucleus of the stria terminalis (BNST), the central amygdala (CeA) and the shell of the nucleus accumbens (NAc) (Heimer and Alheid, 1991, Koob and Le Moal, 2001), has been related to the behavioral and physiological responses associated with reward and stress (Koob, 2008), whereas the hypothalamic stress system, centered by the PVN, has been implicated in the regulation of neuroendocrine responses to stress and stress-induced reinstatement of drug self-administration (Koob and Kreek, 2007). Both systems commonly contain corticotropin releasing factor (CRF) neurons and receive noradrenergic innervations that has been regarded to be critical for stress in addiction (Dunn and Swiergiel, 2008, Holsboer and Ising, 2008, Wood and Woods, 2007). Enhanced responsiveness of HPA axis after morphine withdrawal, which results in an increase in CRF transcription and boost of adrenocorticotropin and corticosterone secretion, has been associated with activation of noradrenergic neurons in the nucleus of tractus solitarius (NTS) and VLM that project to PVN (Laorden et al., 2002a, Laorden et al., 2002b). Noradrenaline (NA) would modulate the release of CRF in the CeA, BNST and PVN and CRF from these nuclei would induce the release of NA by the brainstem noradrenergic areas (Koob, 1999a, Stinus et al., 2005), which are implicated in the cardiac function. Increased CRF release at HPA axis and extrahypothalamic regions occurs in morphine withdrawal (Koob and Le Moal, 2008, Navarro-Zaragoza et al., 2010, Ueno et al., 2011, García-Pérez et al., 2012), the CRF release at HPA axis produces elevated glucocorticoid levels which mediate somatic and negative affective-like components of withdrawal (Contarino and Papaleo, 2005, Harris and Aston-Jones, 2007, Papaleo et al., 2007, Koob, 2008). Because CRF elicits both behavioral and autonomic aspects of the stress response, excessive activation of the CRF system represents a putative mechanism which could contribute to the cardiovascular alterations observed in heroin addict.